Aripiprazole once-monthly long-acting injectable for the treatment of schizophrenia

Introduction: Patient non-adherence increases the risk for relapse and the long-term care of schizophrenia. Long-acting injectable (LAI) antipsychotics can decrease this risk by ensuring adherence. An extended formulation, aripiprazole 400 mg once-monthly (AOM 400) LAI (AOM LAI), received regulatory approval in the year 2013 for the treatment of schizophrenia. AOM LAI is the first dopamine D₂ partial agonist available in a long-acting formulation for the treatment of schizophrenia.

Areas covered: This review covers data on the efficacy and tolerability/safety of AOM LAI. AOM LAI is a lyophilized powder of aripiprazole, with an elimination half-life of 29.9 – 46.5 days, allowing for a 4-week injection interval. Antipsychotic efficacy was documented in a 12-week double-blind trial (n = 340) and in two maintenance-of-effect trials: a 38-week trial (n = 662) and a 52-week trial (n = 403). The side effect profile is similar to that of oral aripiprazole. Adverse events (≥5% and at least twice that for placebo) were typically mild or moderate and did not lead to discontinuation: increased weight, akathisia, injection site pain and sedation. The 400 mg dose is tolerated by >90% of patients. Injection does not require additional training of health personnel or post-injection observation.

Expert opinion: AOM LAI is an efficacious and well-tolerated antipsychotic treatment for schizophrenia.     

注射用利培酮微球治疗精神分裂症的长期疗效初步观察

目的:考察自然观察过程中注射用利培酮微球(恒德)治疗精神分裂症的长期疗效与安全性。方法:自然观察法对使用注射用利培酮微球的34例精神分裂症患者观察12个月,用自身对照法比较治疗前后的疗效变化。应用阳性症状与阴性症状量表(PANSS)、PANSS总分减分率、临床总体病情严重程度印象量表(CGI-S)和临床总体疗效总评印象量表(CGI-I)评定疗效;用药物不良反应量表(TESS)评定安全性。所有患者在治疗前与治疗后的1,2,3,6,9与12月应用上述量表评定患者的疗效与安全性。结果:PANSS总分及各项因子分、CGI-S平均分在治疗后的2,3,6,9,12月的各个时点与治疗后的1个月比较其差异均有非常显著性(P<0.01),有效率从32%增加到97%,CGI-I被评为显著进步的患者从18%增加到94%。锥体外系反应(EPS)的发生率低,不良反应少见。结论:注射用利培酮微球治疗34例精神分裂症患者经过12个月的临床观察,病情持续稳定且耐受性好,在12个月的维持治疗中无1例复发。     

注射用利培酮微球的作用机制及临床应用

注射用利培酮微球是第一个非典型抗精神病药长效剂型,于2006年进入我国市场。它采用先进的Med isorb(微球体)专利技术,减少了首过效应,提高了生物利用度,减少了吸收和生物代谢的个体差异;其在体内缓慢均匀释放的特性,使患者能保持稳定的稳态血浆药物浓度,即便长期治疗中漏掉1次注射,体内药物也不会突然中断;该药物临床疗效好、不良反应少、安全性高,使患者有较好的依从性,且具有最佳的成本-疗效效益。文中综述了注射用利培酮微球的药动学、药效学、临床疗效、安全性及药物经济学效益的最新研究进展。     

注射用利培酮微球治疗精神分裂症的疗效及安全性观察

目的:探讨注射用利培酮微球治疗精神分裂症的疗效及安全性。方法:选择我院病程在1年以上的48例精神分裂症患者,给予注射用利培酮微球及口服利培酮片剂合并治疗4周,此后单一使用注射用利培酮微球维持治疗8周。采用阳性、阴性症状量表(PANSS)、临床总体印象-严重度量表(CGI-S)、和人际和社会能力量表(PSP)评定疗效,采用不良反应量表(TESS)、锥体外系症状量表、临床实验室检查、生命体征、心电图和体格检查评价安全性。结果:注射用利培酮微球单一使用8周后,其有效率(PANSS减分≥30%)为80.5%,CGI-S平均减分为2.1,PSP增加≥7分的患者比例为85.32%;注射用利培酮微球对体重影响较小,锥体外系不良反应较轻。心电图指标、生命体征及体格检查无明显改变,约7.0%(3/43)的患者出现转氨酶升高。结论:注射用利培酮微球可明显改善患者社会功能,可作为一线抗精神病药物单一使用。     

A further consideration on long-acting injectable versus oral antipsychotics in the treatment of schizophrenia: a narrative review and critical appraisal

ABSTRACT

Introduction: Many patients with schizophrenia exhibit difficulties in maintaining adherence to oral antipsychotics, calling for more reliable drug delivery systems.

Areas covered: While non-randomized studies have indicated consistent effectiveness of long-acting injectable antipsychotics (LAIs) over oral counterparts to prevent negative consequences such as relapse, hospitalization and all-cause discontinuation, efficacy results from randomized controlled comparative trials have not been that impressive. The results rely heavily on the study design and the population studied. Further, LAIs are frequently used as an adjunctive to ongoing other antipsychotics or psychotropics, but not solely, in the real world.

Expert opinion: To put LAI–oral comparisons into clinical context, the following information is urgently necessary: (1) How LAIs compare with each other in head-to-head comparisons? (2) How effective is it to switch among different LAIs? (3) How early in the treatment stage should LAIs be utilized? (4) How long the interval of LAI administration can be extended? (5) How LAIs compare with clozapine in head-to-head comparisons? (6) How effective are LAIs when clozapine is ineffective? (7) How effective is clozapine when LAIs are ineffective? (8) How effective is it to combine clozapine and LAIs when neither is effective alone? This paper narratively discusses these critical perspectives.     

Evaluation of patient support program and adherence to long-acting injectable aripiprazole for patients utilizing injection local care centers

Objective: Patient support programs, such as the ASSURE Program for long-acting injectable aripiprazole, are designed to help support access to medications, including long-acting injectable (LAI) antipsychotics for patients with schizophrenia. This study was conducted to evaluate adherence to long-acting injectable aripiprazole among patients utilizing the program local care centers (LCC).

Methods: Data collected from participating LCC between October 2014 and February 2018 were utilized. Characteristics of patients receiving injections at LCC and participating in additional support services of the program, types of program offering utilized and patient cost share for long-acting injectable aripiprazole were described. Adherence, measured as the proportion of days covered (PDC) during follow-up, was estimated in patients utilizing the LCC for 6 months and 9 months. Patients with PDC ≥80% were considered adherent to treatment.

Results: Two hundred and thirty-four patients received at least one injection at participating LCC and enrolled in the patient support program. Mean (SD) age was 37.3 (13.5) years; 60.7% were male; 32.5% were covered by Medicare. In total, 157 and 87 patients were actively utilizing the LCC for at least 6 months and 9 months, respectively. PDC of 97% and 98% were reported among patients with 6 months and 9 months of follow-up, respectively, and patients were considered adherent to long-acting injectable aripiprazole during follow-up.

Conclusion: Patients utilizing the LCC demonstrated high medication adherence, suggesting that injection services provided by the centers may reduce barriers to treatment and help patients with schizophrenia remain on LAI antipsychotic treatment.     

帕利哌酮与阿立哌唑治疗青少年首发精神分裂症的临床对照研究

目的比较帕利哌酮与阿立哌唑治疗青少年首发精神分裂症的临床疗效及安全性。方法 68例青少年首发精神分裂症患者随机分为帕利哌酮组和阿立哌唑组,每组34例。帕利哌酮组起始剂量3 mg·d~(-1),剂量范围3～12 mg·d~(-1);阿立哌唑组起始剂量2.5 mg·d~(-1),剂量范围2.5～20 mg·d~(-1),治疗12周。于基线及2、4、8、12周末,采用阳性与阴性症状量表(PANSS)、个人和社会功能量表(PSP)评定疗效,采用副反应量表(TESS)评价不良反应。结果最终有63例纳入分析,其中帕利哌酮组32例,阿立哌唑组31例。帕利哌酮组治疗总显效率为72%,阿立哌唑组为68%,疗效无显著差异(P>0.05)。治疗12周末时两组PANSS总分、阳性症状分、阴性症状分和一般精神病理症状分均较治疗前有显著下降(P<0.05或P<0.01),组间比较无显著差异(P>0.05)。两组PANSS减分在治疗2周末比较有显著差异(P<0.01),其余时间点比较无显著差异(P>0.05)。两组PSP值均比治疗前显著增高(P<0.01),帕利哌酮组增高更明显,组间比较有显著差异(P<0.05)。两组不良反应发生率无显著差异(72%vs.70%,P>0.05)。结论帕利哌酮治疗青少年首发精神分裂症疗效与阿立哌唑相当,且起效快,安全性高。     

Long-acting injectable antipsychotics in the treatment of schizophrenia: their role in relapse prevention

Importance of the field: Antipsychotic medications are the cornerstone of treatment in schizophrenia, and a large body of data confirms the value of ongoing and continuous antipsychotic pharmacotherapy in controlling symptoms and preventing relapse. However, nonadherence with antipsychotic treatment is a significant issue, with estimates as high as 90%.

Areas covered in this review: This review focuses on long-acting injectable (LAI) antipsychotics and their role in the treatment of schizophrenia. The existing literature, with an emphasis on clinical evidence, is assessed. This includes both reviews and specific trials that examine LAIs and compare them with oral agents, with measures ranging from relapse and rehospitalization to adherence. Both advantages and limitations (e.g., challenges in terms of dose titration and time to steady state) are examined.

What the reader will gain: This overview serves as an update for clinicians wishing to understand LAIs better, including the newer second-generation antipsychotics (SGAs) with this formulation available, and their potential role in the long-term treatment of individuals with schizophrenia.

Take home message: Despite identified advantages, LAIs are not used as widely as might be expected. It would seem that clinicians are at least partly responsible for this, influenced by our own misperceptions (e.g., that LAIs are not acceptable to patients) and, perhaps, misinformation (e.g., increased side effect risk). As clinicians, we may well be shortchanging LAIs if we position them as a treatment of last resort for the multi-episode, nonadherent, ‘revolving door’ patient, especially given recent evidence underscoring their potential benefits in first-episode patients. The search for new and more effective antipsychotics will continue, but we are reminded that suboptimal outcomes may have as much to do with nonadherence as inadequate treatments. Evidence has established that LAI antipsychotics demonstrate distinct benefits in this regard, and we would be remiss if we did not exploit this already available strategy. As well as additional research, we need to rethink how we position these agents in our treatment algorithms if we are to maximize their potential.     

Aripiprazole: the evidence of its therapeutic impact in schizophrenia

INTRODUCTION: An ideal antipsychotic would rapidly stabilize acute psychotic symptoms and maintain the patient, without relapse, for prolonged periods in the absence of extrapyramidal, endocrine, diabetic, or cardiovascular side effects, and without weight gain. The dopamine partial agonist aripiprazole is compared with this ideal and with conventional antipsychotics, such as haloperidol, and with atypical antipsychotics. AIMS: To review the evidence for the clinical impact of aripiprazole in the treatment of patients with schizophrenia. EVIDENCE REVIEW: There is clear evidence that aripiprazole is as effective as haloperidol in reducing the positive and negative symptoms of schizophrenia and schizoaffective disorder. In patients with schizophrenia, aripiprazole has been shown to stabilize acute psychotic symptoms, prevent relapse in stabilized patients, and maintain patients with schizophrenia following acute relapse. Furthermore, in common with other atypical antipsychotics, aripiprazole appears to be associated with a lower incidence of side effects than typical antipsychotics and may reduce discontinuation of drug therapy. Evidence also suggests that aripiprazole may be associated with a lower incidence of extrapyramidal symptoms than conventional antipsychotics, but further long-term studies concerning tardive dyskinesia are required. Studies on the cost effectiveness of aripiprazole, as well as the quality of life and general functioning of patients taking the drug are still required, although there is some evidence of improved quality of life. Further evidence comparing aripiprazole with other atypical antipsychotics would be welcome. CLINICAL VALUE: In conclusion, aripiprazole is an atypical antipsychotic suitable for first-line use in patients with schizophrenia. Its clinical value in relation to other atypical antipsychotics remains to be elucidated.     

Long-acting atypical injectable antipsychotics in the treatment of schizophrenia: safety and tolerability review

Importance of the field: Although atypical antipsychotics have beneficial efficacy and tolerance, non-adherence and partial adherence remain in patients treated for schizophrenia. Long-acting injectable or depot atypical antipsychotics offer better medication adherence and tolerability advantages. Currently, two drugs are available for the treatment of schizophrenia, risperidone long-acting injectable (RLAI) and olanzapine pamoate (OP).

Areas covered in this review: Short- and long-term safety and tolerability data on RLAI and OP from January 2006 through September 2009 were reviewed by performing Medline and PubMed searches, reviewing abstracts and poster presentations, and viewing available material from the FDA and European Medicines Agency.

What the reader will gain: RLAI and OP show good short- and long-term safety when treating patients with schizophrenia, with uncommon discontinuation due to adverse effects. RLAI and OP data show rare problems with injection site reactions and patients exposed to injectable treatments prefer to continue injections. Infrequent but serious post-injection delirium sedation syndrome occurred after 1% of OP injections. Weight gain was generally higher among patients treated with OP versus RLAI.

Take home message: Healthcare providers, patients and family members should be made aware of the safety and benefits of long-acting injectable atypical antipsychotics in order to diminish the unnecessary restrictions of these therapies for patients with schizophrenia.     

Healthcare resource utilization of second-generation long-acting injectable antipsychotics in schizophrenia: risperidone versus paliperidone palmitate

Objective: This retrospective longitudinal cohort study aimed to compare treatment patterns, healthcare resource utilization (HRU), and costs in patients with schizophrenia treated with second-generation antipsychotic long-acting injectables (SGA-LAIs): biweekly risperidone LAI versus once-monthly paliperidone palmitate.

Methods: Patients who initiated risperidone LAI or paliperidone palmitate between 1 July 2007 and 31 December 2012 (index date) were identified from the Truven MarketScan Commercial, Medicare Supplemental, and Medicaid Multi-State insurance databases. Outcomes were assessed 12 months after the index date. Propensity score matching (1:1) based on patients’ demographics and comorbidities was conducted. Outcome differences between the two cohorts were evaluated using t-tests for continuous variables, chi-square tests for categorical variables, and Wilcoxon rank-sum tests for count and cost variables. Regression models estimated the difference in medication use and adherence, likelihood of HRU, number of HRU events, and healthcare costs when comparing risperidone LAI versus paliperidone palmitate, while further adjusting for patient characteristics and pre-index HRU.

Results: Patient characteristics were well balanced between the two cohorts (n?=?499 each). Significantly lower discontinuation rates (36.5% vs. 53.3%; p?<?0.001) and longer days of LAI coverage (233.6 vs. 131.7 days; p?<?0.001) were observed in the paliperidone palmitate cohort versus the risperidone LAI cohort, respectively. Patients treated with paliperidone palmitate were 12.5 (95% confidence interval [CI]: 9.0–17.8) and 11.7 (95% CI: 8.0–17.4) times more likely to be adherent based on medication possession ratio and proportion of days covered, respectively (p?<?0.001). Patients treated with paliperidone palmitate had reduced likelihood of hospitalization (adjusted odds ratio [95% CI]: 0.72 [0.55–0.95]), fewer emergency department (ED) visits (adjusted incidence rate ratio [aIRR]: 0.67 [0.61–0.73]) and reduced length of inpatient stay (aIRR: 0.86 [0.82–0.90]), which resulted in lower monthly inpatient hospitalization costs (-$77.58; p?=?0.038) and ED visits (-$9.77; p?=?0.021) relative to risperidone LAI.

Limitations: Pharmacy costs were derived from health plan payment in the claims data and do not account for any discounts or rebates. This may have overestimated the branded drug costs in this analysis.

Conclusions: These findings highlight the value of once-monthly paliperidone palmitate in the treatment of patients with schizophrenia.     

阿立哌唑治疗精神分裂症的开放性临床验证

目的验证阿立哌唑治疗精神分裂症的有效性及安全性。方法用可变剂量阿立哌唑治疗精神分裂症45例,剂量范围5～30mg/d,疗程共8周;以PANSS量表、临床疗效总评量表(CGI)评定疗效;以治疗药物副作用量表(TESS)评定药物不良反应。结果45例中36例完成8周疗程,9例在4周内停止使用。治疗结束时,显效率为64.4%(29/45),其中临床痊愈31.1%(14/45),显著进步33.3%(15/45),好转22.2%(10/45),无变化13.3%(6/45)。阿立哌唑治疗精神分裂症常见不良反应为焦虑、静坐不能、头晕、乏力、视物模糊、震颤等。结论阿立哌唑治疗精神分裂症有效、安全,不良反应少,可作为临床治疗精神分裂症的一种选择。     

阿立哌唑治疗老年精神分裂症的疗效和安全性观察

目的:观察阿立哌唑治疗老年精神分裂症的临床疗效和安全性。方法:70例老年精神分裂症患者随机分为以下2组:阿立哌唑组[男性17例,女性18例,年龄(66.2±2.4)岁]和氟哌啶醇组[男性18例,女性17例,年龄(65.4±2.4)岁]。阿立哌唑组和氟哌啶组的起始剂量分别为5~10mg/d和2mg/d,之后视病情分别调整为(12.8±3.3)mg/d和(7.3±3.6)mg/d,共治疗8周。采用阳性症状与阴性症状量表(PANSS)评定临床疗效,用不良反应症状量表(TESS)评定不良反应。结果:阿立哌唑组与氟哌啶醇组的有效率分别为88.6%和85.7%,2组比较差异无统计学意义(P>0.05)。阿立哌唑组不良反应少而轻微。结论:阿立哌唑为治疗老年精神分裂症的有效安全药物。     

阿立哌唑治疗晚发精神分裂症的疗效观察及其对认知功能的影响

目的:探讨阿立哌唑与利培酮对晚发精神分裂症的疗效及安全性,并比较它们对认知功能的影响。方法:45例晚发精神分裂症患者随机分为阿立哌唑组与利培酮组,其中阿立哌唑组21例使用阿立哌唑10～30 mg·d~(-1),利培酮组24例使用利培酮3～4 mg·d~(-1),分别采用阳性阴性症状评定量表(PANSS)及药物副反应量表(TESS)进行疗效及安全性评定,并于治疗前后测定事件相关电位。结果:阿立哌唑组总有效率71.4%,利培酮组总有效率75.0%,两组间疗效无统计学差异(P>0.05)。治疗前两组患者的事件相关电位与正常对照组比较有统计学差异(P<0.05),治疗后两组患者的事件相关电位与正常对照组比较,差异均无统计学意义。不良反应量表(TESS)两组比较无统计学差异。结论:阿立哌唑与利培酮治疗晚发精神分裂症疗效相当,不良反应轻,且对认知功能影响轻微。     

阿立哌唑与利培酮治疗精神分裂症的对照研究

目的：比较阿立哌唑与利培酮治疗精神分裂症的疗效和安全性。方法：对符合《中国精神障碍分类与诊断标准》第3版（CCMD-3）精神分裂症诊断标准的50例患者,随机分为两组,分别给予阿立哌唑和利培酮治疗共8周。采用阳性与阴性症状量表（PANSS）和不良反应量表（TESS）评分。结果：治疗8周后阿立哌唑组和利培酮组的显效率分别为72％和76％,差异无显著性（P〉0．05）。两组治疗后各时点PANSS总分及各因子分也无显著性差异（P〉0．05）。阿立哌唑组的主要不良反应为恶心,厌食,呕吐等消化道症状,而锥体外系反应明显低于利培酮组。结论：阿立哌唑和利培酮对精神分裂症疗效相当,不良反应轻,均为疗效好的抗精神病药,阿立哌唑更适合于锥体外系副作用不能耐受的患者。     

阿立哌唑与利培酮治疗精神分裂症的双盲双模拟多中心研究

目的:研究阿立哌唑与利培酮治疗精神分裂症的疗效与安全性。方法:采用CCMD-3精神分裂症的诊断标准,223例精神分裂症患者随机分为阿立哌唑组(109例)和利培酮组(114例),治疗6周。治疗前后用阳性症状和阴性症状量表(PANSS)、临床疗效总评量表(CGI)和副反应量表(TESS)、锥体外系副反应量表(ESRS)评定疗效和安全性。结果:经6周治疗,223例患者完成研究。阿立哌唑组治愈率31.8%,有效率83.3%;利培酮组治愈率39.1%,有效率87.5%(P>0.05)。两组治疗前后PANSS总分、阳性症状、阴性症状、一般精神病理症状评分比较有显著差异(P<0.01)。阿立哌唑组阴性症状分治疗6周末下降较利培酮组明显,有显著差异(P<0.05)。治疗4周末、6周末阿立哌唑组反应缺乏分下降,和利培酮组比较有显著差异(P<0.05)。治疗4,6周末TESS评定阿立哌唑不良反应发生率低于利培酮(P<0.05)。阿立哌唑组主要不良反应是锥体外系副反应、失眠、头昏等。结论:阿立哌唑对精神分裂症患者安全有效。